DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statement filed July 31, 2024 is acknowledged and has been considered by the examiner.
Claim Objections
Claims 128, 137, 139, and 144 are objected to because of the following informalities:
In claim 128, line 12 of this claim provides structure options for the group Rz3. However, among the structures Rz3 is permitted to be includes another recitation of “Rz3.” In view of the following clause reciting Rz3* and the structure of the provided definition for Rz1 in the lines above this clause, it appears the asterisk is missing in what should be the first recitation of Rz3* but is instead a repeated recitation of Rz3.
Claims 137 and 139, as written, end with commas. Per MPEP § 608.01(m), each claim must end with a period.
In claim 137, lines 2 and 4 of the claim recite “C3-8cyckoalkyl.” In view of the other claim limitations and the applications as a whole, this appears to be a typographical error and should be revised to C3-8cycloalkyl.
In claim 144, line 11 of this claim ends with a period, but the claim continues with more limitations following the period and ends with another period at the end of line 15. In view of the claim as a whole, it appears the first period is a typographical error and that the Applicant intends for claim 144 to include all 15 lines.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 128-144 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 128 provides a wide scope of molecules that could possess the donor-linker-acceptor structure as claimed. However, it is not clear that all potential structures within the scope of this claim would possess similar properties contemplated within the application. Some of the claimed functional groups for the many R groups are electron withdrawing, electron donating, and aromatic in ways that would alter the conjugation system of the molecule; all of which could have an impact on the optical properties of the compound. Indeed, Zhang (Zhang, J.; et al., J. Mater. Chem. C, 2020) teaches that seemingly small changes to amine substituents connecting to the middle of the polyene linking group (and substitution of chlorine for such amine groups) can have an impact on the absorbance and emission wavelengths of the dye and the Stokes shift of the molecule (Tables 1 and 2). Additionally, Kulinich (Kulinich, A. V.; J. Photochem. Photobiol. A, 2014) teaches that donor strength, acceptor strength, and length of conjugation system alter the properties of similar dyes (Table 1). Furthermore, Bublitz (Bublitz, G. U.; J. Am. Chem. Soc., 1997) teaches that changes to donor and acceptor strengths and conjugation length impacts the properties of similar dyes, suggesting that these factors shift the ground state from a more polyene-like state to a cyanine-like state (pg. 3365, Abstract and structure depiction in left column; Table 1; and Figures 4, 5, and 6). Additionally, Oushiki (Oushiki, D.; et al., J. Am. Chem. Soc., 2010) teaches that modification to donor and linker groups can significantly alter a dye’s oxidation potential (Table 1). In view of these references, it is understood that substitution of fluorophores in donor, acceptor, and linker regions can have profound impacts on their properties and function.
Furthermore, per MPEP § 2163, an inventor can show possession by describing the claimed invention using words, structures, figures, diagrams, and formulas. The examiner notes that several specific structures have been provided, particularly on pages 66-70 of the specification. However, these disclosed species are not representative of the entire genus of molecules being claimed in claim 128. For example, in all species disclosed, R1 and R2 are H; none of the other claimed embodiments for these moieties are disclosed. Similarly, Re, Rd, and Rf are also H in all disclosed examples. Additionally, in none of the species disclosed are there any Rc groups within the scope of claim 138. Furthermore, the depicted structures only provide examples in the scope of claim 135 wherein Rc is the third of the four listed structures in that claim. Additionally, the depicted structures only provide examples in the scope of claim 144 wherein the acceptor is the first provided structure of the four listed in that claim. Furthermore, all figures describe properties of some of the molecules provided on pages 66-70 of the specification, so the properties of the non-depicted structures are not described. It is not apparent that the properties of these other embodiments are contemplated.
As many claimed structure options are missing from the disclosed embodiments, the examiner considers the disclosure to lack a representative number of species for the broad genus claimed in claim 128. Therefore, it is understood that the specification does not provide sufficient written support to describe all embodiments of the claimed compounds. Additionally, Claims 129-144 are also rejected due to their dependency on the scope of claim 128. While each of these claims narrow the structure in some way, the way these are claimed and the dependencies provided means that in each of these dependent claims, only one of the donor, acceptor, or linker are being narrowed in scope; while for the aforementioned reasons, there is a lack of written description in all of these components. Thus, while one group may be narrowed in a dependent claims, the description issues for the other groups persist. Therefore, the disclosure does not provide sufficient written support to describe all embodiments of each of these claims.
Scope of Enablement
Claim 146 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the therapeutic treatment of triple negative breast cancer (TNBC) with a few molecules within the scope of claim 128 comprising administering a therapeutically effective amount of the compounds, does not reasonably provide enablement for the prevention of any cancer with any compounds of claim 128 at any dose, the therapeutic treatment of any cancer with most of the compounds of claim 128, the therapeutic treatment of other cancers with the limited species that may be enabled for the treatment of TNBC, the therapeutic treatment of any non-cancer proliferative disorder, or the therapeutic treatment of any cancer with any compound of claim 128 at non-therapeutically effective doses of administration. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.” Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. These factors include, but are not limited to:
The breadth of the claims;
The nature of the invention;
The state of the prior art;
The level of one of ordinary skill;
The level of predictability in the art;
The amount of direction provided by the inventor;
The existence of working examples; and
The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427, F.2d 833, 839, 166 USPQ 18, 24 (1970). To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention, state and predictability of the art, and relative skill level
The invention of claim 146 relates to a method of treating a proliferative disorder in a subject in need thereof. The method involves the administration of a compound of claim 128 to said subject. Claim 128 is drawn to a wide scope of compounds that are fluorescent dyes.
The relative skill of those in the art who would use such compounds is high, likely that of one who has obtained at a Ph.D. or M.D.
In the art, it is understood that small changes to the structure of a fluorophore can impart meaningful changes to its properties. As described above, Zhang teaches that changes to amine substituents connecting to the middle of the polyene linking group can impact on the absorbance and emission wavelengths of a dye and the Stokes shift of the molecule (Tables 1 and 2). Additionally, Kulinich teaches that donor strength, acceptor strength, and length of conjugation system alter the properties of similar dyes (Table 1). Furthermore, Bublitz teaches that changes to donor and acceptor strengths and conjugation length impacts the properties of similar dyes, suggesting that these factors shift the ground state from a more polyene-like state to a cyanine-like state (pg. 3365, Abstract and structure depiction in left column; Table 1; and Figures 4, 5, and 6). Additionally, Oushiki teaches that modification to donor and linker groups can significantly alter a dye’s oxidation potential (Table 1). In view of these references, it is understood that substitution of fluorophores in donor, acceptor, and linker regions can have profound impacts on their properties as it relates to fluorescence.
Furthermore, it is understood in the pharmaceutical arts that most experimentally developed drugs follow “the rule of 5” (Lipinski, C. A.; et al., Adv. Drug Delivery Rev., 1997; hereinafter referred to as “Lipinski”). Lipinski teaches that changes in drug structure changes physico-chemical properties of the molecule (Section 2.1). Lipinski teaches that poor pharmaceutical properties are present when there are more than 5 hydrogen bond donors, the molecular weight is over 500 g/mol, the LogP is over 5, and there are more than 10 hydrogen bond acceptors (pg. 9, left column). Thus, changes in these properties through the changing of an R group of a molecule can impact its suitability as a pharmaceutical compound.
Additionally, it is understood in the pharmaceutical arts, that in order for a cytotoxic compound to exert a therapeutic effect, there needs to be a mechanism by which it accumulates in the diseased tissue more than it does in healthy tissue; otherwise the compound would be highly toxic to such healthy tissue. Frangioni teaches that small modification to cyanine dye derivatives significantly impacts what tissues the dyes accumulate in in vivo (Figures 1-58). This suggests that modifications within the scope of claim 128 would result in changes as to what tissue the compound may be able to target. This is in agreement with the teachings of Lipinski that small changes to molecular structure can alter physicochemical properties.
Furthermore, it is generally understood that no single compound or class of molecules can effectively treat any and all cancers. Solid tumors differ from blood cancers and different cancers metastasize differently. Even within one class of cancers, there can be subcategorization. For example, there are several forms of breast cancers, including hormone sensitive, HER2+, and TNBC (BCRF, 2016; herein after referred to as “BCRF”). Furthermore, BCRF teaches that compounds that treat one form of breast cancer may not be effective in the treatment of other forms of breast cancers. For example, BCRF states that tamoxifen can be used to treat hormone sensitive breast cancers, but not those lacking a functional estrogen receptor, such as TNBC (paragraphs 2-4). Similarly, BCRF teaches that trastuzumab can be used in HER2+ breast cancers, but not TNBC. The teachings of BCRF provide an example that even within a cancer class, the efficacy of a compound to treat one subclass does not guarantee it will be effective in treating a different subclass. Similarly, just because a compound can be used to treat one cancer does not mean it can be used in the treatment of other cancers.
To the examiner’s understanding, little is known in the art regarding the anti-proliferative properties of compounds within the scope of claim 128. However, the examiner notes that Essam (Essam, Z. M.; et al., Org. Biomol. Chem., 2021 – provided by applicant in IDS filed July 31, 2024) teaches molecules within the scope of claim 128 (see corresponding 102 rejection below) and teaches the cytotoxic property of four such compounds in cell lines derived from TNBC (Table 2; Figure 8; and Figure 9). Specifically, Essam teaches that compounds 4, 7, 10, and 12 (Scheme 2 and reproduced below) are the molecules that possess this property. To the
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examiner’s understanding, the teachings of Essam indicate that these four molecules have the potential to be used in the therapeutic treatment of TNBC, as they demonstrate cytotoxicity of model TNBC cells in vitro. Essam does not provide any data supporting the utility of these four compounds in any other cancer or proliferative disorder. Furthermore, in light of the teachings of BCRF, it is not apparent that the four compounds of Essam would reasonably be expected to work for other proliferative disorders. It is also not apparent in the teachings of Essam or other available art that other compounds of Essam or other compounds within the scope of claim 128 possess cytotoxic, anti-proliferative, or anti-cancer properties.
There is generally a lack of predictability in the pharmaceutical art. In re Fisher, 427, F. 2d 833, 166, USPQ 18 (CCPA 1970). While predictions can be made regarding how ligands will bind receptors or molecules target cells in silico, these are inconsistent at determining if a molecule will be able to exert a pharmacological effect in a living biological subject.
The breadth of the claims
Claim 146 is broad insofar as the scope encompasses the treatment of any proliferative disorder. This includes, but is not limited to cancers. The examiner considers all cancers to be within the scope of the claim as provided. There are many non-cancer proliferative disorders such as non-cancerous hyperplasia.
Furthermore, on pg. 23 of the instant specification, the Applicant defines that “treating” and “treatment” include the scope of prophylaxis and prevention of a disease. This is reiterated on pg. 60 of the instant specification. Therefore, the scope of claim 146 as written includes both the therapeutic treatment of a proliferative disorder already present and the prevention of a proliferative disorder that is not present in a subject. To this extent, the examiner understands the scope of claim 146 to encompass the prevention of any and all cancers.
Additionally, the process of claim 146 as claimed just requires the administration of a compound of claim 128, but uses “comprising” language, which means that other steps may be performed. This means the claim includes in its scope combination therapy using a compound of claim 128 with other compounds, such as chemotherapeutic compounds. Additionally included within the scope of the claim is fluorescence guided surgery to remove a tumor. In the simplest form of the claim though, it includes administration of the compounds of claim 128 as single agents without additional steps being performed.
Furthermore, the scope of claim 146 includes administration of a compound of claim 128 in any amount. No dosage is provided as a limitation in this claim. Therefore, doses ranging from picograms to kilograms and beyond this range are within the scope of claim 146. While the lack of a dosage or amount limitation in claim 146 means that the scope does include therapeutically effective amounts of compounds of claim 128, it also means it includes sub-therapeutically effective amounts and toxic amounts of such compounds, which would both be therapeutically ineffective.
Additionally, claim 146 is broad in scope due to the breadth of the molecules claims in claim 128. Claim 128 contains a core structure of a donor, linker, and acceptor, but contains many R groups with many structural options at each R group, meaning the number of possible molecules within the scope of claim 128, and thus for use in claim 146, is very large. Within the scope of claim 146 is the use of any and all of the compounds of claim 128. This includes a wide range of molecules with different charge states, molecular weights, polarities, absorbances, emission wavelengths, Stokes shifts, fluorescence intensities, photodynamic properties, toxicities, anti-proliferative activities, and pharmacokinetic properties.
The amount of direction or guidance provided and the presence or absence of working examples
The specification provides little direction or guidance for practicing the claimed invention in its “full scope.” No working examples are provided for the use of any compounds of claim 128 in the treatment of a proliferative disorder in a subject. No working examples of administration of any compounds of claim 128 to a subject are provided. No working examples of the use of any compounds of claim 128 in the prevention of a proliferative disorder are provided. No working examples of the use of any compounds of claim 128 in combination with other therapeutic steps in the therapeutic treatment of a proliferative disease are provided.
The direction and guidance provided on pages 56-61 of the instant specification is very broad, such that it could apply to nearly all molecules and is not particular to the disclosed species or any contemplated embodiment of claim 128. The mere statement in the last paragraph of pg. 56 of the instant specification that “the disclosed compounds can have cytotoxic properties” does not teach that all compounds of claim 128 possess these properties, nor does it provide evidence that any of the compounds of claim 128 possess this property.
The quantity of experimentation necessary
Experimentation to determine a therapeutically effective amount of material to administer to a subject can be significant. Furthermore, determining if any given compound is effective for treatment of certain diseases may span long periods of time. Determining if any given compound is effective for the prevention of proliferative diseases requires significant sample sizes and long study durations. Furthermore, identification of which of the many proliferative disorders a given compound can treat would require significant experimentation and many different model systems. As the scope of claim 128 encompasses a very large number of molecules, the determination of pharmacokinetic properties, toxicity profiles, formulations, and effective administration methods would be significant because identification of a particularly effective compound within such a broad range would require the testing of thousands (or likely more) compounds.
Conclusion
Because of the known state of the art and the absence of experimental evidence and working examples, it is apparent that the amount of experimentation required to determine which of the claimed structures could be used in the claimed methods of treatment would be efficacious, which proliferative disorders could be treated, and the amount of the compound to administer is very significant and unreasonable due to the breadth of the molecules being claimed, steps that may be performed, and disorders claimed.
Accordingly, the instant claims do not comply with the enablement requirement of §112(a), since to practice the claimed invention in its “full scope,” a person of ordinary skill in the art would have to engage in an unreasonable amount of experimentation, with no reasonable expectation of success.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 128, 130-134, 139-142, and 145 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yan (Yan, J.; et al., Chem. Commun., 2017).
Yan teaches merocyanine-based near-infrared fluorescent probes (pg. 9910, Abstract). More specifically, Yan teaches the dyes labeled as MC-1 and MC-1 in Scheme 1 (pg. 9911).
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Yan describes that these molecules possess an electron donor, a long pi-conjugated system, and an acceptor and that the dyes display a red shift on excitation and emission (pg. 9911, left column, first paragraph). Yan also teaches performing in vivo imaging in mice using MC-1 (pg. 9912, Figure 4).
Regarding claim 128, MC-1 (pg. 9911, Scheme 1) reads on the compound of claim 128 wherein Z2 is N-Rzd and Rzd is C1 alkyl; Z1 is C(Rz)2 wherein each Rz is C1 alkyl; R1 is R1a, R2 is R2a, R3 is R3a, and R4 is R4a, wherein each of R1a, R2a, R3a, and R4a are hydrogen; X1 and X2 are both Q-CN wherein Q is null; Re is Re1, Rd is Rd1, and Rf is Rf1 wherein each of Re1, Rd1, and Rf1 are hydrogen; Rc is Cl; and both Ra and Rb can be considered to be either C1-3 alkyl or cycloalkyl. The embodiment of MC-1 therefore anticipates the compound of claim 128. Furthermore, MC-2 (pg. 9911, Scheme 1) reads on the compound of claim 128 wherein Z2 is N-Rzd and Rzd is C1 alkyl; Z1 is C(Rz)2 wherein each Rz is C1 alkyl; R1 is R1a, R2 is R2a, R3 is R3a, and R4 is R4a, wherein each of R1a, R2a, R3a, and R4a are hydrogen; X1 is Q-CN wherein Q is null; X2 is Q-C(=O)ORx2 wherein Q is null and Rx2 is C2 alkyl; Re is Re1, Rd is Rd1, and Rf is Rf1 wherein each of Re1, Rd1, and Rf1 are hydrogen; Rc is Cl; and both Ra and Rb can be considered to be either C1-3 alkyl or cycloalkyl. The embodiment of MC-2 therefore also anticipates the compound of claim 128.
Regarding claim 130, MC-1 of Yan (pg. 9911, Scheme 1) reads on the linker of claim 130 wherein Re is Re1, Rd is Rd1, and Rf is Rf1 wherein each of Re1, Rd1, and Rf1 are hydrogen; Rc is Cl; A1 is C(Ra1)2, wherein each Ra1 is Ra1$, wherein each Ra1$ is hydrogen; A2 is C(Ra2)2, wherein each Ra2 is Ra2$, wherein each Ra2$ is hydrogen; and A3 is C(Ra3)2, wherein each Ra3 is Ra3$, wherein each Ra3$ is hydrogen. Therefore, MC-1 anticipates the structure of claim 130. Furthermore, MC-2 of Yan (pg. 9911, Scheme 1) reads on the linker of claim 130 wherein Re is Re1, Rd is Rd1, and Rf is Rf1 wherein each of Re1, Rd1, and Rf1 are hydrogen; Rc is Cl; A1 is C(Ra1)2, wherein each Ra1 is Ra1$, wherein each Ra1$ is hydrogen; A2 is C(Ra2)2, wherein each Ra2 is Ra2$, wherein each Ra2$ is hydrogen; and A3 is C(Ra3)2, wherein each Ra3 is Ra3$, wherein each Ra3$ is hydrogen. Therefore, MC-2 also anticipates the structure of claim 130.
Regarding claim 131, in both compounds MC-1 and MC-2 of Yan (pg. 9911, Scheme 1), A2 is CHRa2, wherein Ra2 is Ra2$, wherein Ra2$ is hydrogen; A1 is CH2; and A3 is CH2.
Regarding claim 132, both compounds MC-1 and MC-2 of Yan (pg. 9911, Scheme 1) contain the linker of claim 132 wherein Qa is null and Ra2 is H.
Regarding claim 133, in both compounds MC-1 and MC-2 of Yan (pg. 9911, Scheme 1), Rd and Rf are both hydrogen.
Regarding claim 134, in both compounds MC-1 and MC-2 of Yan (pg. 9911, Scheme 1), Rc is Cl.
Regarding claim 139, in both compounds MC-1 and MC-2 of Yan (pg. 9911, Scheme 1), Z2 is N-Rzd wherein Rzd is C1 alkyl and Z1 is C(Rz)2 wherein each Rz is C1 alkyl.
Regarding claim 140, in both compounds MC-1 and MC-2 of Yan (pg. 9911, Scheme 1), Z1 is C(CH3)2.
Regarding claim 141, in compound MC-1 of Yan (pg. 9911, Scheme 1), both X1 and X2 are CN.
Regarding claim 142, in compound MC-2 of Yan (pg. 9911, Scheme 1), X1 is CN and X2 is Q2-CO2C2alkyl wherein Q2 is null.
Regarding claim 145, Yan teaches preparing MC-1 and MC-2 in PBS (pg. 9911, left column, third paragraph). The examiner interprets PBS to be a buffering agent and a diluent. On page 61 of the instant specification, Applicant states that pharmaceutical excipients include buffering agents and diluents. Therefore, the examiner interprets a solution of MC-1 and MC-2 to anticipate a pharmaceutical composition comprising a compound of claim 128 and at least one pharmaceutically acceptable excipient.
Claim 147 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yan, as evidenced by Davidson (Davidson, M. W.; et al., Molecular Expressions, 2015).
As described above, Yan teaches merocyanine-based near-infrared fluorescent probes (pg. 9910, Abstract). More specifically, Yan teaches the dyes labeled as MC-1 and MC-1 in Scheme 1 (pg. 9911). Yan describes that these molecules possess an electron donor, a long pi-conjugated system, and an acceptor and that the dyes display a red shift on excitation and emission (pg. 9911, left column, first paragraph). Yan also teaches performing in vivo imaging in mice using MC-1 (pg. 9912, Figure 4).
Davidson teaches basic concepts in fluorescence microscopy (Title). More specifically, Davidson teaches that fluorescence is the property of a molecule to absorb light and subsequently emit light (first paragraph). Davidson teaches that fluorescence requires excitation of a susceptible molecule by an incoming photon (second paragraph).
Regarding claim 147, Yan teaches in vivo imaging using MC-1 in mice (pg. 9912, Figure 4). Yan teaches that the compound was administered by intravenous injection (pg. 9912, left column, third paragraph). Yan teaches that fluorescence signals from the brain were recorded, which the examiner interprets to mean that living tissue was imaged. As evidenced by Davidson (second paragraph), generation of a fluorescence signal requires excitation with light. Thus, the method of Yan is interpreted by the examiner to require irradiation of the compound with light.
Claims 128-134, 139-140, 142-143, and 145 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Essam (Essam, Z. M.; et al., Org. Biomol. Chem., 2021 – provided by applicant in IDS filed July 31, 2024).
Essam teaches donor-pi-acceptor fluorophores (pg. 1835, Abstract). Essam teaches that such fluorophores are modular and can be prepared using different donors and acceptors (pg. 1836, Figures 1 and 2). Specifically, Essam teaches fluorophores 4-20 (pg. 1837, Scheme 2, reproduced below).
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Essam teaches that some of these fluorophores possess cytotoxic properties and can kill immortalized triple negative breast cancer cells in culture (pg. 1842, Figure 8; and pg. 1843, Evaluation of anti-proliferative activity of TNBC cell lines).
Regarding claim 128, each of the fluorophores 4-18 of Essam (Scheme 2) anticipate the compound of claim 128. The fluorophores each contain the same linker and acceptor regions wherein Re is Re1, Rd is Rd1, and Rf is Rf1 wherein each of Re1, Rd1, and Rf1 are hydrogen; Rc is Cl; both Ra and Rb can be considered to be either C1-3 alkyl or cycloalkyl; X1 is Cl; and X2 is Q-C(=O)ORx2 wherein Rx2 is H.
In fluorophores 4-11, the donor group reads on that of claim 128 wherein Z1 is C(Rz)2 wherein each Rz is C1 alkyl and R1 is R1a, R2 is R2a, and R4 is R4a, wherein each of R1a, R2a, and R4a are hydrogen. Furthermore, in each of these structures, Z2 is N-Rzd. In fluorophores 4, 6, and 10, Rzd is C1 alkyl. In fluorophores 7, 8, and 9, Rzd is C2 alkyl, which is substituted in fluorophore 9. In fluorophores 5 and 11, Rzd is C4 alkyl. Additionally, in fluorophores 4 and 5, R3 is R3a wherein R3a is hydrogen. In fluorophores 6, 7, and 9, R3 is Br. In fluorophore 8, R3 is Cl. In fluorophores 10 and 11, R3 is OR3a wherein R3a is C1 alkyl.
In fluorophores 12-15, the donor group reads on that of claim 128 wherein Z1 is S and R1 is R1a, R2 is R2a, and R4 is R4a, wherein each of R1a, R2a, and R4a are hydrogen. Furthermore, in each of these structures, Z2 is N-Rzd. In fluorophores 12, Rzd is C2 alkyl. In fluorophore 13, Rzd is C6 alkyl. In fluorophore 14, Rzd is C1 alkyl. In fluorophore 15, Rzd is C4 alkyl. Additionally, in fluorophores 12, 13, and 15, R3 is R3a wherein R3a is hydrogen. In fluorophore 14, R3 is Br.
In fluorophores 16 and 17, the donor group reads on that of claim 128 wherein Z1 is C(Rz)2 wherein each Rz is C1 alkyl; and wherein R1 is R1a and R2 is R2a wherein each of R1a and R2a are hydrogen. In each of these structures, R3 and R4 are R3a and R4a, which are aryl. Furthermore, in each of these structures, Z2 is N-Rzd. In fluorophore 16, Rzd is C1 alkyl. In fluorophore 17, Rzd is C6 alkyl.
In fluorophores 18, the donor group reads on that of claim 128 wherein Z1 is C(CRz1)=C(CRz1) wherein each Rz1 is Rz1*, which is hydrogen. Furthermore, R1 is R1a, R2 is R2a, and R4 is R4a, wherein each of R1a, R2a, and R4a are hydrogen. Furthermore, structure 18, Z2 is N-Rzd. In fluorophore 18, Rzd is C1 alkyl. Additionally, in fluorophore 18, R3 is C(O)OR3a wherein R3a is hydrogen.
For these reasons, the embodiments of fluorophores 4-18 of Essam therefore anticipate the compound of claim 128.
Regarding claim 129, in fluorophores 6-9, 14, and 18 of Essam (Scheme 2), each of R1, R2, and R4 are hydrogen. In fluorophores 6, 7, 9, and 14, R3 is Br. In fluorophore 8, R3 is Cl. In fluorophore 18, R3 is C(O)OR3a wherein R3a is hydrogen.
Regarding claim 130, fluorophores 4-18 of Essam (Scheme 2) all contain the same linker region structure. In each of these linkers, Re is Re1, Rd is Rd1, and Rf is Rf1 wherein each of Re1, Rd1, and Rf1 are hydrogen; Rc is Cl; A1 is C(Ra1)2, wherein each Ra1 is Ra1$, wherein each Ra1$ is hydrogen; A2 is C(Ra2)2, wherein each Ra2 is Ra2$, wherein each Ra2$ is hydrogen; and A3 is C(Ra3)2, wherein each Ra3 is Ra3$, wherein each Ra3$ is hydrogen.
Regarding claim 131, in fluorophores 4-18 of Essam (Scheme 2), A2 is CHRa2, wherein Ra2 is Ra2$, wherein Ra2$ is hydrogen; A1 is CH2; and A3 is CH2.
Regarding claim 132, fluorophores 4-18 of Essam (Scheme 2) contain the linker of claim 132 wherein Qa is null and Ra2 is H.
Regarding claim 133, in each of fluorophores 4-18 of Essam (Scheme 2), Rd and Rf are both hydrogen.
Regarding claim 134, in each of fluorophores 4-18 of Essam (Scheme 2), Rc is Cl.
Regarding claim 139, in each of fluorophores 4-11, 16, and 17 of Essam (Scheme 2), Z2 is N-Rzd as described above and Z1 is C(Rz)2 wherein each Rz is C1 alkyl. In each of fluorophores 12-15, Z2 is N-Rzd as described above and Z1 is S. In fluorophore 18, Z2 is N-Rzd wherein Rzd is C1 alkyl and Z1 is C(CRz1)=C(CRz1) wherein each Rz1 is Rz1*, which is hydrogen.
Regarding claim 140, in each of fluorophores 4-11, 16, and 17 of Essam (Scheme 2), Z1 is C(CH3)2.
Regarding claim 142, in each of fluorophores 4-18 of Essam (Scheme 2), X1 is Cl and X2 is Q2-CO2H wherein Q2 is null.
Regarding claim 143, in each of fluorophores 4-18 of Essam (Scheme 2), X1 is Cl and X2 is -CO2H.
Regarding claim 145, Essam teaches preparing fluorophores 4, 7, 10, and 12 in DMSO for the cell culture and cytotoxic assays (Supplemental material, pg. 9). The examiner interprets DMSO to be a diluent. On page 61 of the instant specification, Applicant states that pharmaceutical excipients include diluents. Therefore, the examiner interprets the solutions of fluorophores 4, 7, 10, and 12 of Essam in DMSO to anticipate a pharmaceutical composition comprising a compound of claim 128 and at least one pharmaceutically acceptable excipient.
Claims 128, 133-134, 139-140, and 144 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bublitz (Bublitz, G.; et al., J. Am. Chem. Soc., 1997).
Bublitz teaches donor/acceptor merocyanine dyes (pg. 3365, Abstract). Bublitz teaches that changing the donor and acceptor strengths influence the electron localization along the polyene linker group (pg. 3365, Introduction, second paragraph). Bublitz teaches the study of 12 polyene dye compounds (pg. 3366, Figure 1).
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Regarding claim 128, each of compounds 4, 5, 6, and 8 of Bublitz (Figure 1) read on the compound of claim 128 wherein Z2 is N-Rzd and Rzd is C1 alkyl; Z1 is C(Rz)2 wherein each Rz is C1 alkyl; R1 is R1a, R2 is R2a, R3 is R3a, and R4 is R4a, wherein each of R1a, R2a, R3a, and R4a are hydrogen; and Re is Re1, Rd is Rd1, Ra is Ra1, Rc is Rc1, Rb is Rb1, and Rf is Rf1 wherein each of Re1, Rd1, Ra1, Rc1, Rb1, and Rf1 are hydrogen. Each of these compounds differs from each other in the acceptor region of the structure, but each also reads on the structure of claim 128. In compound 4, X1 and X2 are Q-C(=O)Rx1 and Q-C(=O)Rx2 wherein Q is null and Rx1 and Rx2 can each be interpreted to be an aryl moiety. In compound 5, X1 and X2 are Q-C(=O)ORx1 and C(=O)ORx2 wherein Q is null and Rx1 and Rx2 are both substituted C1 alkyl. In compounds 6 and 8, X1 and X2 are Q-C(=O)N(Rx1)2 and Q-C(=O)N(Rx2)2 wherein Q is null and the two Rx1 and Rx2 groups on each nitrogen are substituted C1 alkyl and unsubstituted C2 alkyl.
Regarding claim 133, in each of compounds 4, 5, 6, and 8 of Bublitz (Figure 1), Rd and Rf are both hydrogen.
Regarding claim 134, in each of compounds 4, 5, 6, and 8 of Bublitz (Figure 1), Rc is Rc1 wherein Rc1 is hydrogen.
Regarding claim 139, in each of compounds 4, 5, 6, and 8 of Bublitz (Figure 1), Z2 is N-Rzd wherein Rzd is C1 alkyl and Z1 is C(Rz)2 wherein each Rz is C1 alkyl.
Regarding claim 140, in each of compounds 4, 5, 6, and 8 of Bublitz (Figure 1), Z1 is C(CH3)2.
Regarding claim 144, each of compounds 4, 6, and 8 of Bublitz (Figure 1) have an acceptor structure that reads on the first of the four depicted formulas of claim 144. More specifically, in compound 4, X#1 and X#2 are each oxo and X$ is aryl. In compound 6, X#1 and X#2 are each oxo and X$ is -NR#3-C(=O)-NR#3- wherein each R#3 is C2 alkyl. In compound 8, X#1 and X#2 are each oxo and X$ is -NR#3-C(=S)-NR#3- wherein each R#3 is C2 alkyl.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 128, 130-137, and 139-142 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (Zhang, J.; et al., J. Mater. Chem. C, 2020) in view of Yan (Yan, J.; et al., Chem. Commun., 2017).
Zhang teaches cyanine fluorescent dyes (pg. 16769, Abstract). Zhang provides an analysis of the effect of nitrogen substituents on the Stokes shift of cyanine dyes (pg. 16769, Results and discussion, first paragraph, first sentence). Specifically, Zhang teaches 17 compounds (dyes 2-8, 9-15, and 16-18) possessing amine functional groups attached to the polyene chain in the dyes possessing different donor substituents (pg. 16770, Tables 1 and 2).
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Zhang teaches that changing these nitrogen groups changes the Stokes shift of these molecules (pg. 16770, Tables 1 and 2). Zhang teaches that selectively engineering Stokes shift in cyanine dyes is important to imaging applications (pg. 16772-16773, Conclusions).
Zhang does not teach dye molecules possessing an acceptor moiety containing X1 and X2 as defined in claim 128 of the instant application.
As described above, Yan teaches merocyanine-based near-infrared fluorescent probes (pg. 9910, Abstract). More specifically, Yan teaches the dyes labeled as MC-1 and MC-1 in Scheme 1 (pg. 9911).
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Yan describes that these molecules possess an electron donor, a long pi-conjugated system, and an acceptor and that the dyes display a red shift on excitation and emission (pg. 9911, left column, first paragraph). Yan also describes that these molecules are modified derivatives of IR-780 (pg. 9911, Scheme 1). Yan teaches that the substitution of the charged acceptor group of IR-780 for the di-cyano or cyano and ester acceptor moieties confers upon the molecule the ability to penetrate the blood brain barrier (pg. 9911, left column, second paragraph), which is typically not possible for symmetrical cyanine dyes due to the cationic moiety (pg. 9910, right column, third paragraph). Yan also teaches performing in vivo imaging in mice using MC-1 (pg. 9912, Figure 4).
A person of ordinary skill in the art would have recognized that both Zhang and Yan teach cyanine dyes and cyanine derivatives for imaging purposes. It would be recognized that the dyes of Zhang are similar to IR-780 disclosed in Yan, containing the cationic amine group that Yan substitutes.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the amine-modified linker containing cyanine dyes of Zhang with the uncharged acceptor moieties of Yan in place of the charged groups because Yan teaches this modification to be an improvement on cyanine dyes like those of Zhang to alter biodistribution (MPEP § 2143(I)(C)). This combination would have yielded the predictable result of a donor-linker-acceptor fluorescent dye modified with an amine group in the linker and containing an uncharged, cyano-containing acceptor moiety.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this modification because Yan teaches making this modification to a symmetrical cyanine dye (IR-780), which is similar to the dyes of Zhang in structure. IR-780 is particularly similar to dyes 2-8 of Zhang.
The skilled artisan would have been motivated to make this modification because Yan teaches this modification alters biodistribution, enabling access to the brain in vivo for imaging.
Regarding claim 128, each of dyes 2-8 of Zhang (Table 1) contain donor groups wherein Z2 is N-Rzd and Rzd is C1 alkyl; Z1 is C(Rz)2 wherein each Rz is C1 alkyl; R1 is R1a, R2 is R2a, R3 is R3a, and R4 is R4a, wherein each of R1a, R2a, R3a, and R4a are hydrogen. Each of dyes 9-15 of Zhang (Table 2) contain donor groups wherein Z2 is N-Rzd and Rzd is C2 alkyl; Z1 is C(Rz)2 wherein each Rz is C1 alkyl; R1 is R1a and R2 is R2a, wherein each of R1a and R2a is hydrogen; and R3 and R4 are R3a and R4a, which are aryl. Each of dyes 16-18 of Zhang (Table 2) contain donor groups wherein Z2 is N-Rzd and Rzd is C2 alkyl; Z1 is S; and R1 is R1a, R2 is R2a, R3 is R3a, and R4 is R4a, wherein each of R1a, R2a, R3a, and R4a are hydrogen.
Additionally, Yan teaches an acceptor group wherein either X1 and X2 are both Q-CN wherein Q is null (MC-1) or X1 is Q-CN wherein Q is null; X2 is Q-C(=O)ORx2 wherein Q is null and Rx2 is C2 alkyl (MC-2) (Scheme 1).
If the charged groups in the dyes of Zhang is substituted for the acceptor of Yan in the same way Yan teaches the modification of IR-780, the resulting structures would possess a linker that reads on that of claim 128 wherein ; Re is Re1, Rd is Rd1, and Rf is Rf1 wherein each of Re1, Rd1, and Rf1 are hydrogen; and both Ra and Rb can be considered to be either C1-3 alkyl or cycloalkyl. The Rc groups in the linkers of Zhang vary, but all are within the scope of N(Rc1)2. These structures include embodiments in which each Rc1 is independently C1 or C2 alkyl or wherein Rc1 is C2-5 heterocyclyl.
Therefore, the combined teachings of Zhang and Yan render claim 128 obvious.
Regarding claim 130, the linkers of Zhang (Tables 1 and 2) read on the structure of claim 130 wherein Re is Re1, Rd is Rd1, and Rf is Rf1 wherein each of Re1, Rd1, and Rf1 are hydrogen; Rc is N(Rc1)2 as described above; A1 is C(Ra1)2, wherein each Ra1 is Ra1$, wherein each Ra1$ is hydrogen; A2 is C(Ra2)2, wherein each Ra2 is Ra2$, wherein each Ra2$ is hydrogen; and A3 is C(Ra3)2, wherein each Ra3 is Ra3$, wherein each Ra3$ is hydrogen. Therefore, the combined teachings of Zhang and Yan render claim 130 obvious.
Regarding claim 131, in the linkers of Zhang (Tables 1 and 2), A2 is CHRa2, wherein Ra2 is Ra2$, wherein Ra2$ is hydrogen; A1 is CH2; and A3 is CH2. Therefore, the combined teachings of Zhang and Yan render claim 131 obvious.
Regarding claim 132, the linkers of Zhang (Tables 1 and 2) contain the linker of claim 132 wherein Qa is null and Ra2 is H. Therefore, the combined teachings of Zhang and Yan render claim 132 obvious.
Regarding claim 133, in each of the dyes of Zhang (Tables 1 and 2), Rd and Rf are both hydrogen. Therefore, the combined teachings of Zhang and Yan render claim 133 obvious.
Regarding claim 134, in each of dyes of Zhang (Tables 1 and 2), Rc is N(Rc1)2. Therefore, the combined teachings of Zhang and Yan render claim 134 obvious.
Regarding claim 135, in dyes 8 and 15 of Zhang (Tables 1 and 2), the linker contains an Rc group matching that of the third in the list of structures of this claim wherein each Rc4 is Rc4$ wherein each Rc4$ is hydrogen. Therefore, the combined teachings of Zhang and Yan render claim 135 obvious.
Regarding claim 136, in dyes 8 and 15 of Zhang (Tables 1 and 2), the linker contains an Rc group as defined in claim 136 wherein Rc4 is Rc4$ wherein Rc4$ is hydrogen. Therefore, the combined teachings of Zhang and Yan render claim 136 obvious.
Regarding claim 137, in dyes 2, 3, 6, 9, 10, 13, 16, and 17 of Zhang (Tables 1 and 2), the linker contains an Rc group wherein Rc is NRc1Rc2 wherein each Rc1 and Rc2 is independently C1 or C2 alkyl. Therefore, the combined teachings of Zhang and Yan render claim 137 obvious.
Regarding claim 139, in each of dyes 2-8 of Zhang (Tables 1 and 2), Z2 is N-Rzd wherein Rzd is C1 alkyl and Z1 is C(Rz)2 wherein each Rz is C1 alkyl. In dyes 9-15, Z2 is N-Rzd wherein Rzd is C2 alkyl and Z1 is C(Rz)2 wherein each Rz is C1 alkyl. In dyes 16-18, Z2 is N-Rzd wherein Rzd is C2 alkyl and Z1 is S. Therefore, the combined teachings of Zhang and Yan render claim 139 obvious.
Regarding claim 140, in each of dyes 2-15 of Zhang (Tables 1 and 2), Z1 is C(CH3)2. Therefore, the combined teachings of Zhang and Yan render claim 140 obvious.
Regarding claim 141, Yan teaches compound MC-1 (pg. 9911, Scheme 1), which possesses an acceptor moiety wherein both X1 and X2 are CN. Therefore, the combined teachings of Zhang and Yan render claim 141 obvious.
Regarding claim 142, Yan teaches compound MC-2 (pg. 9911, Scheme 1), which possesses an acceptor moiety wherein X1 is CN and X2 is Q2-CO2C2alkyl wherein Q2 is null. Therefore, the combined teachings of Zhang and Yan render claim 142 obvious.
Claims 128, 130-134, and 138-142 are rejected under 35 U.S.C. 103 as being unpatentable over Oushiki (Oushiki, D.; et al., J. Am. Chem. Soc., 2010) in view of Yan.
Oushiki teaches cyanine dyes and derivatives of said dyes (pg. 2795, Abstract). More specifically, Oushiki teaches derivatives of Cy5 and Cy7 (pg. 2798, Figure 4) and their reactivities with reactive oxygen species (pg. 2797, Table 1). Oushiki teaches that a thioether modification in the middle of a polymethine chain, producing IR768S (Figure 4 and depicted below) significantly reduces the oxidation
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potential of the dye, increasing its reactivity with reactive oxygen species (Table 1 and pg. 2797, right column, first paragraph; and pg. 2798, Figure 7). Oushiki teaches further modifying IR768S to generate probe for in vivo imaging of oxidative stress (pg. 2799, Scheme 1; and pg. 2801, Figures 11 and 12).
Oushiki does not teach dye molecules possessing an acceptor moiety containing X1 and X2 as defined in claim 128 of the instant application.
As described above, Yan teaches merocyanine-based near-infrared fluorescent probes (pg. 9910, Abstract). More specifically, Yan teaches the dyes labeled as MC-1 and MC-1 in Scheme 1 (pg. 9911).
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Yan describes that these molecules possess an electron donor, a long pi-conjugated system, and an acceptor and that the dyes display a red shift on excitation and emission (pg. 9911, left column, first paragraph). Yan also describes that these molecules are modified derivatives of IR-780 (pg. 9911, Scheme 1). Yan teaches that the substitution of the charged acceptor group of IR-780 for the di-cyano or cyano and ester acceptor moieties confers upon the molecule the ability to penetrate the blood brain barrier (pg. 9911, left column, second paragraph), which is typically not possible for symmetrical cyanine dyes due to the cationic moiety (pg. 9910, right column, third paragraph). Yan also teaches performing in vivo imaging in mice using MC-1 (pg. 9912, Figure 4).
A person of ordinary skill in the art would have recognized that both Oushiki and Yan teach cyanine dyes and cyanine derivatives for imaging purposes. It would be recognized that the IR768S dye of Oushiki is structurally similar to IR-780 disclosed in Yan, containing a similar cationic amine group to that which Yan substitutes.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the thioether-modified low oxidation potential cyanine dye of Oushiki with the cyano group-containing acceptor moieties of Yan in place of the positively charged groups because Yan teaches this modification to be an improvement on cyanine dyes like those of Oushiki to alter biodistribution (MPEP § 2143(I)(C)). This combination would have yielded the predictable result of a donor-linker-acceptor fluorescent dye modified with a thioether group in the linker and containing a cyano-containing acceptor moiety.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this modification because Yan teaches making this modification to a symmetrical cyanine dye (IR-780), which is similar to the IR768S dye structure of Oushiki.
The skilled artisan would have been motivated to make this modification because Yan teaches this modification alters biodistribution, enabling access to the brain in vivo for imaging.
Regarding claim 128, the IR786 dye of Oushiki (Figure 4) contains a donor group wherein Z2 is N-Rzd and Rzd is C1 alkyl; Z1 is C(Rz)2 wherein each Rz is C1 alkyl; R1 is R1a, R2 is R2a, R3 is R3a, and R4 is R4a, wherein each of R1a, R2a, R3a, and R4a are hydrogen. Additionally, Yan teaches acceptor groups wherein either X1 and X2 are both Q-CN wherein Q is null (MC-1) or X1 is Q-CN wherein Q is null; X2 is Q-C(=O)ORx2 wherein Q is null and Rx2 is C2 alkyl (MC-2) (Scheme 1). Furthermore, if the positively charged amine-containing group in IR768S of Oushiki is substituted for the acceptor of Yan in the same way Yan teaches the modification of IR-780, the resulting structures would possess a linker that reads on that of claim 128 wherein ; Re is Re1, Rd is Rd1, and Rf is Rf1 wherein each of Re1, Rd1, and Rf1 are hydrogen; and both Ra and Rb can be considered to be either C1-3 alkyl or cycloalkyl. The Rc group in the linker of Oushiki is SRc1 wherein Rc1 is C3 alkyl that is substituted. Therefore, the combined teachings of Oushiki and Yan render claim 128 obvious.
Regarding claim 130, the linker of IR768S of Oushiki (Figure 4) reads on the structure of claim 130 wherein Re is Re1, Rd is Rd1, and Rf is Rf1 wherein each of Re1, Rd1, and Rf1 are hydrogen; Rc is SRc1 wherein Rc1 as described above; A1 is C(Ra1)2, wherein each Ra1 is Ra1$, wherein each Ra1$ is hydrogen; A2 is C(Ra2)2, wherein each Ra2 is Ra2$, wherein each Ra2$ is hydrogen; and A3 is C(Ra3)2, wherein each Ra3 is Ra3$, wherein each Ra3$ is hydrogen. Therefore, the combined teachings of Oushiki and Yan render claim 130 obvious.
Regarding claim 131, in the linker of IR768S of Oushiki (Figure 4), A2 is CHRa2, wherein Ra2 is Ra2$, wherein Ra2$ is hydrogen; A1 is CH2; and A3 is CH2. Therefore, the combined teachings of Oushiki and Yan render claim 131 obvious.
Regarding claim 132, the linker of IR768S of Oushiki (Figure 4) contains the linker of claim 132 wherein Qa is null and Ra2 is H. Therefore, the combined teachings of Oushiki and Yan render claim 132 obvious.
Regarding claim 133, in IR768S of Oushiki (Figure 4), Rd and Rf are both hydrogen. Therefore, the combined teachings of Oushiki and Yan render claim 133 obvious.
Regarding claim 134, in IR768S of Oushiki (Figure 4), Rc is SRc1. Therefore, the combined teachings of Oushiki and Yan render claim 134 obvious.
Regarding claim 138, in IR768S of Oushiki (Figure 4), ), Rc is SRc1wherein Rc1 is CH2CH2COOH. Therefore, the combined teachings of Oushiki and Yan render claim 138 obvious.
Regarding claim 139, in IR768S of Oushiki (Figure 4), Z2 is N-Rzd wherein Rzd is C1 alkyl and Z1 is C(Rz)2 wherein each Rz is C1 alkyl. Therefore, the combined teachings of Oushiki and Yan render claim 139 obvious.
Regarding claim 140, in IR768S of Oushiki (Figure 4), Z1 is C(CH3)2. Therefore, the combined teachings of Oushiki and Yan render claim 140 obvious.
Regarding claim 141, Yan teaches compound MC-1 (pg. 9911, Scheme 1), which possesses an acceptor moiety wherein both X1 and X2 are CN. Therefore, the combined teachings of Oushiki and Yan render claim 141 obvious.
Regarding claim 142, Yan teaches compound MC-2 (pg. 9911, Scheme 1), which possesses an acceptor moiety wherein X1 is CN and X2 is Q2-CO2C2alkyl wherein Q2 is null. Therefore, the combined teachings of Oushiki and Yan render claim 142 obvious.
Claim 146 is rejected under 35 U.S.C. 103 as being unpatentable over Sun (Zhang, X.; … Sun, J.; et al., Bioact. Mater., 2021) in view of Essam.
Sun teaches cancer phototherapy (pg. 2291, Abstract). More specifically, Sun teaches the preparation of nanoparticles containing a pair of the cyanine dye DiR and another fluorophore (pg. 2292-2293, Figures 1 and 2). Sun teaches that Ce6 and DiR are a FRET pair of fluorophores (pg. 2294, Figure 3). Sun teaches that nanoparticles containing Ce6 and DiR accumulated in xenograft tumors of triple negative breast cancer in mice (pg. 2296, Section 2.7 and Figure 5). Sun teaches that performing photodynamic therapy using these nanoparticles decreases the rate of tumor growth (pg. 2298, Figure 7).
Sun does not teach a method of treating cancer comprising administering a compound of claim 128.
As described above, Essam teaches donor-pi-acceptor fluorophores (pg. 1835, Abstract). Essam teaches that such fluorophores are modular and can be prepared using different donors and acceptors (pg. 1836, Figures 1 and 2). Specifically, Essam teaches fluorophores 4-20 (pg. 1837, Scheme 2, reproduced below).
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Essam teaches that some of these fluorophores possess cytotoxic properties and can kill immortalized triple negative breast cancer cells in culture (pg. 1842, Figure 8; and pg. 1843, Evaluation of anti-proliferative activity of TNBC cell lines).
A person of ordinary skill in the art would have recognized that both Sun and Essam teach anti-proliferative uses of polymethine dyes. It would also be recognized that both teach models of triple negative breast cancer.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the dual-fluorophore nanoparticle photodynamic therapy of Sun by substituting DiR for one of the dyes of Essam, because these dyes are of similar structure and would serve the same purpose in the nanoparticle system (MPEP § 2143(I)(B)). This would yield the predictable result of a nanoparticle therapy including the dyes of Essam.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this modification because Sun teaches that several dyes can be used in preparing such nanoparticles. Additionally, DiR is similar in structure to the dyes of Essam.
The skilled artisan would have been motivated to make this modification because Essam teaches dyes 4, 7, 10, and 12 can kill immortalized TNBC cell lines in vitro. This suggests that if the fluorophore pair nanoparticles degrade in vivo, the fluorophores of Essam may be able to continue to exert an anti-tumor effect.
Regarding claim 146, Sun teaches a method of treating a xenograft tumor model of TNBC in a mouse model wherein photodynamic therapy of dye-containing nanoparticles results in a decrease in tumor growth (pg. 2298, Figure 7). The examiner interprets treatment of cancer to read on treating a proliferative disorder. This comprises administering nanoparticles containing fluorescent molecules multiple times (Figure 7A). Additionally, as described above, Essam teaches molecules that anticipate claim 128. Therefore, incorporation of compound 4, 7, 10, or 12 of Essam in the nanoparticle of Sun would result in a method comprising administering a compound of claim 128 to a subject in need thereof. Therefore, the combined teachings of Sun and Essam render claim 146 obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 128-134, 139-142, and 147 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 9,023,611 B2 in view of Yan (Yan, J.; et al., Chem. Commun., 2017).
Claims 128-134, 139-142, and 147 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 2 of U.S. Patent No. 9,687,567 B2 in view of Yan (Yan, J.; et al., Chem. Commun., 2017).
Claims 128-129, 133-134, 139-142, and 145 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11 and 12 of U.S. Patent No. 11,572,475 B2 in view of Yan (Yan, J.; et al., Chem. Commun., 2017).
Claims 128-134, 139-142, 146, and 147 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 11,738,095 B2 in view of Yan (Yan, J.; et al., Chem. Commun., 2017).
The claims of conflicting patents US 9,023,611 B2; US 9,687,567 B2; US 11,572,475 B2; and US 11,738,095 B2 are drawn to cyanine dyes, pharmaceutic compositions containing cyanine dyes, methods of imaging using cyanine dyes, and methods of treating cancer using cyanine dyes.
The claims of these conflicting patents do not teach dyes containing acceptor groups that read on the acceptor group of claim 128 of the instant application.
As described above, Yan teaches merocyanine-based near-infrared fluorescent probes (pg. 9910, Abstract). More specifically, Yan teaches the dyes labeled as MC-1 and MC-1 in Scheme 1 (pg. 9911). Yan describes that these molecules possess an electron donor, a long pi-conjugated system, and an acceptor and that the dyes display a red shift on excitation and emission (pg. 9911, left column, first paragraph). Yan also describes that these molecules are modified derivatives of IR-780 (pg. 9911, Scheme 1). Yan teaches that the substitution of the charged acceptor group of IR-780 for the di-cyano or cyano and ester acceptor moieties confers upon the molecule the ability to penetrate the blood brain barrier (pg. 9911, left column, second paragraph), which is typically not possible for symmetrical cyanine dyes due to the cationic moiety (pg. 9910, right column, third paragraph). Yan also teaches performing in vivo imaging in mice using MC-1 (pg. 9912, Figure 4).
A person of ordinary skill in the art would have recognized that each of conflicting patents US 9,023,611 B2; US 9,687,567 B2; US 11,572,475 B2; and US 11,738,095 B2 and Yan teach cyanine dyes and cyanine derivatives for imaging purposes. It would be recognized that the dyes of the conflicting patents are structurally similar to IR-780 disclosed in Yan, containing a similar cationic amine group to that which Yan substitutes.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the cyanine dyes of the conflicting U.S. patents with the cyano group-containing acceptor moieties of Yan in place of the positively charged groups because Yan teaches this modification to be an improvement on cyanine dyes like those of the conflicting patents to alter biodistribution (MPEP § 2143(I)(C)). This combination would have yielded the predictable result of a donor-linker-acceptor fluorescent dye modified containing a cyano-containing acceptor moiety.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this modification because Yan teaches making this modification to a symmetrical cyanine dye (IR-780), which is similar to the dye structures of the conflicting patents.
The skilled artisan would have been motivated to make this modification because Yan teaches this modification alters biodistribution, enabling access to the brain in vivo for imaging, and removes a positive charge from the molecule.
With respect to conflicting U.S. Patent No. 9,023,611 B2, conflicting claim 2 is drawn to a dye that reads on the donor and linker groups of instant claims 128, 129, 130, 131, 132, 133, 134, 139, and 140. Additionally, as described above, Yan teaches acceptor groups that read on instant claims 141 and 142. Furthermore, conflicting claims 1 and 5 of U.S. Patent No. 9,023,611 B2 are drawn to methods of imaging living tissue using these dyes and reads on instant claim 147.
With respect to conflicting U.S. Patent No. US 9,687,567 B2, conflicting claim 2 is drawn to a dye that reads on the donor and linker groups of instant claims 128, 129, 130, 131, 132, 133, 134, 139, and 140. Additionally, as described above, Yan teaches acceptor groups that read on instant claims 141 and 142. Furthermore, conflicting claim 1 of U.S. Patent No. 9,687,567 B2 are drawn to a method of imaging living tissue using these dyes and reads on instant claim 147.
With respect to conflicting U.S. Patent No. US 11,572,475 B2, conflicting claims 11 and 12 are drawn to pharmaceutical compositions containing cyanine dyes wherein the dyes possess structures that read on the donor and linker groups of instant claims 128, 129, 133, 134, 139, and 140. Additionally, as described above, Yan teaches acceptor groups that read on instant claims 141 and 142. Furthermore, as these are drawn to pharmaceutical compositions, these also read on instant claim 145.
With respect to conflicting U.S. Patent No. US 11,738,095 B2, conflicting claims 1 and 11 are drawn to methods of imaging cancer cells and treating cancer using cyanine dyes. The dyes of these claims and dependent conflicting claims 2-10 and 12-22 are dyes that possess donor and linker groups that read on those claimed in instant claims 128, 129, 130, 131, 132, 133, 134, 139, and 140. Additionally, as described above, Yan teaches acceptor groups that read on instant claims 141 and 142. Furthermore, as conflicting claims 1 and 11 of U.S. Patent No. 11,738,095 B2 are drawn to methods of imaging cells and treating cancer using these dyes, they read on instant claims 147 and 146, respectively.
Claims 128-135, 137, 139-142, and 145-147 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2 and 14-20 of copending Application No. 18/730,243 in view of Yan (Yan, J.; et al., Chem. Commun., 2017).
Claims 128-134, 139-142, and 145-147 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-9, 11-12, 15-16, 21-23, 25-28, and 31 of copending Application No. 19/129,441 in view of Yan (Yan, J.; et al., Chem. Commun., 2017).
The claims of copending applications 18/730,243 and 19/129,441 are drawn to cyanine dyes, pharmaceutic compositions containing cyanine dyes, methods of imaging using cyanine dyes, and methods of treating cancer using cyanine dyes.
The claims of these copending applications do not teach dyes containing acceptor groups that read on the acceptor group of claim 128 of the instant application.
As described above, Yan teaches merocyanine-based near-infrared fluorescent probes (pg. 9910, Abstract). More specifically, Yan teaches the dyes labeled as MC-1 and MC-1 in Scheme 1 (pg. 9911). Yan describes that these molecules possess an electron donor, a long pi-conjugated system, and an acceptor and that the dyes display a red shift on excitation and emission (pg. 9911, left column, first paragraph). Yan also describes that these molecules are modified derivatives of IR-780 (pg. 9911, Scheme 1). Yan teaches that the substitution of the charged acceptor group of IR-780 for the di-cyano or cyano and ester acceptor moieties confers upon the molecule the ability to penetrate the blood brain barrier (pg. 9911, left column, second paragraph), which is typically not possible for symmetrical cyanine dyes due to the cationic moiety (pg. 9910, right column, third paragraph). Yan also teaches performing in vivo imaging in mice using MC-1 (pg. 9912, Figure 4).
A person of ordinary skill in the art would have recognized that each of copending applications 18/730,243 and 19/129,441 and Yan teach cyanine dyes and cyanine derivatives for imaging purposes. It would be recognized that the dyes of the copending applications are structurally similar to IR-780 disclosed in Yan, containing a similar cationic amine group to that which Yan substitutes.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the cyanine dyes of the copending applications with the cyano group-containing acceptor moieties of Yan in place of the positively charged groups because Yan teaches this modification to be an improvement on cyanine dyes like those of the conflicting patents to alter biodistribution (MPEP § 2143(I)(C)). This combination would have yielded the predictable result of a donor-linker-acceptor fluorescent dye modified containing a cyano-containing acceptor moiety.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this modification because Yan teaches making this modification to a symmetrical cyanine dye (IR-780), which is similar to the dye structures of the copending applications.
The skilled artisan would have been motivated to make this modification because Yan teaches this modification alters biodistribution, enabling access to the brain in vivo for imaging, and removes a positive charge from the molecule.
With respect to copending application 18/730,243, conflicting claims 2 and 14 are drawn to a dye that reads on the donor and linker groups of instant claims 128, 129, 130, 131, 132, 133, 134, 135, 137, 139, and 140. Additionally, as described above, Yan teaches acceptor groups that read on instant claims 141 and 142. Furthermore, conflicting claim 15 is drawn to a pharmaceutical composition containing such dyes, which reads on instant claim 145. Additionally, conflicting claims 16-19 are drawn to methods of imaging living tissue using such dyes, which reads on instant claim 147. Furthermore, conflicting claim 20 is drawn to a method of treating cancer comprising administering such dyes, which reads on instant claim 146.
With respect to copending application 19/129,441, conflicting claim 1 and dependent claims 2-6, 8-9, 11-12, 15-16, 21-23, and 25-26 are drawn to dyes that reads on the donor and linker groups of instant claims 128, 129, 130, 131, 132, 133, 134, 139, and 140. Additionally, as described above, Yan teaches acceptor groups that read on instant claims 141 and 142. Furthermore, conflicting claim 27 is drawn to a pharmaceutical composition containing such dyes, which reads on instant claim 145. Additionally, conflicting claim 28 is drawn to a method of imaging cancerous tumor in a subject, which is a living tissue, which therefore reads on instant claim 147. Furthermore, conflicting claim 31 is drawn to a method of treating cancer comprising administering such dyes, which reads on instant claim 146.
These are provisional nonstatutory double patenting rejections.
Pertinent Art
As pertinent art, the examiner cites Kulinich (Kulinich, A. V.; et al., J. Photochem. Photobiol. A, 2014). Kulinich teaches merocyanine dyes (pg. 91, Abstract). Kulinich describes the dyes as a pair of a donor and an acceptor connected by a polymethine chain (pg. 91, right column, second paragraph; and pg. 92, Scheme 1). Specifically, Kulinich discloses the structure of 8 dyes (pg. 94, Scheme 2).
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The examiner notes that these dyes are similar to those disclosed in the above references. In particular, compound 3 of Kulinich contains the same donor and acceptor groups as MC-1 of Yan and contains a linker group of the same length but lacking the cycloalkyl and chlorine modifications.
As pertinent art, the examiner cites Abdel Aal (Abdel Aal, R. M.; et al., Chem. Int. 3, 2017). Abdel Aal teaches cyanine dyes (pg. 358, Abstract). Abdel Aal discloses compound 3, 4, and 5 (pg. 359, Scheme 1):
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which are very similar in structure to the compounds of Yan and Essam discussed above.
As pertinent art, the examiner cites Shishkina (Shishkina, S. V.; et al., Struct. Chem., 2021). Shishkina teaches polymethine dyes (pg. 91, Abstract). Shishkina describes the dyes as a pair of a donor and an acceptor connected by a polymethine chain (pg. 169, right column, third paragraph; and pg. 170, Figure 1). Specifically, Shishkina discloses the structure of 4 dyes (pg. 170, Figure 2).
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The examiner notes that these dyes are similar to those disclosed in the above references. In particular, compound 3 of Shishkina contains the same acceptor groups as MC-1 of Yan and contains a linker group of the same length but lacking the cycloalkyl and chlorine modifications (similar to Kulinich). The donor group of Shishkina compound 3 is similar to that of Yan but Rzd is C2 alkyl and Z1 is S.
As pertinent art, the examiner cites Strell (Strell, M.; et al., Justus Liebigs Annalen der Chemie, 1954). The examiner notes that the reference provided is in a non-English language. However, Strell discloses chemical structures related to the instant application. As most claims of the instant application pertain to molecules possessing certain chemical structures, it is just the chemical structures of Strell that need to be viewed and the content of the words are not needed to understand how the molecules of Strell relate to the instant application. In particular, Table 1 of Strell (pages 6-7) disclose several chemical structures very similar to those in the instant application and claim set and the references applied above.
As pertinent art, the examiner cites Mayerhoffer (Mayerhoffer, U.; et al., Chem. Eur. J., 2013). Mayerhoffer teaches acceptor-substituted squaraine dyes (Title). More specifically, teaches the preparation of squaraine dyes with several different acceptor moieties (pg. 219, Scheme 1; reproduced below).
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The examiner notes that Mayerhoffer teaches a di-cyano acceptor similar to that of Kulinich. Mayerhoffer also teaches acceptors similar to those of Bublitz (especially compound 4 of Bublitz). The examiner notes that the squaraine dyes are similar to those of the instant application, containing similar donors and linker regions.
As pertinent art, the examiner cites MacNevin (MacNevin, C. J.; et al., Bioconjug. Chem., 2013 – provided by applicant in IDS filed July 31, 2024). MacNevin teaches merocyanine dyes (pg. 215, Abstract). More specifically, MacNevin teaches several combinations of different donors and acceptors in the merocyanine dyes (pg. 218, Table 3). These donors and acceptors are very similar in structure to those of the instant application and several of the above cited references. The examiner notes that as MacNevin teaches combining donors and acceptors in a matrix of combinations, it teaches that these moieties are highly interchangeable and modular. The examiner also notes that the molecules of MacNevin contain a polyene linker like the instant claims, but the linker length is different.
Conclusion
No Claim is allowed.
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/E.P.M./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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